PROJECT SUMMARY The vast majority of hearing and balance impairments are thought to be due to death of sensory hair cells, the receptor cells of the inner ear. These cells are unusually metabolically active and hypersensitive to damage from overstimulation, exposure to some therapeutic drugs and environmental toxins, and to aging. Growing evidence indicates that hair cell loss from gram-negative antibiotics, antineoplastic drugs, excessive noise exposure and possibly aging share some common cellular pathways. The goals of our research program, requesting continued funding for Years 16-20, are to understand the pathways that regulate death and survival of inner ear hair cells, and to use this information to facilitate development of therapeutic agents to prevent hearing loss. Three groups of experiments are proposed: a) determine roles of the lysosome in both promoting and preventing damage caused by aminoglycoside antibiotics; b) identify the cellular mechanisms and molecular targets of a new therapeutic drug that protects hair cells against antibiotic-induced ototoxic damage; and c) test whether this new therapeutic will protect in vivo against cisplatin toxicity. An assumption of our work is that highly conserved properties of HC function render them unusually vulnerable to antibiotic and antineoplastic drug toxicity. Thus, in addition to clinical implications for preventing hearing and balance disorders, these studies may also reveal important aspects of normal HC function that give rise to their vulnerability.